Association between intraoperative remifentanil use and postoperative hyperalgesia in adolescent idiopathic scoliosis surgery: a retrospective study

In this retrospective analysis, we did not find any association between the different doses of remifentanil with the occurrence of postoperative hyperalgesia. There were no significant differences in the NRS for pain score at rest and on movement, and morphine consumption between the low and high-dose remifentanil groups.

The relationship between the use of remifentanil in clinical practice and the development of OIH remains controversial, despite the existence of many studies in the past. A review by Kim et al. [11] concluded that multiple issues, including but not limited to the dose and duration of opioids and methods used in assessing pain as the confounding factors. Adding to the gap is a lack of understanding and standard definitions for OIH, opioid tolerance, and withdrawal-associated hyperalgesia, which are often used interchangeably due to their overlapping symptoms [12]. Several methods have been suggested to evaluate the incidence of OIH in the clinical settings, including measuring pain intensity, opioid consumption, evaluation of secondary hyperalgesia using monofilaments and other sensory tests such as cold, heat, vibration, and electrical stimulation [5]. In our study, pain scores and morphine consumption were chosen given their practicality and frequent use in previous studies.

The result of our study is in concert with the finding of a recent observational study who found no association between their relatively high dose and long duration of intraoperative remifentanil (mean total remifentanil dose was 0.12 mg/kg, mean infusion duration was 435 min) and postoperative opioid consumption in adolescent idiopathic spine surgery when used in the context of propofol-based anaesthesia and multimodal analgesia [4]. In a similar type of surgery in adults, Yeom et al. [13] also found no evidence of acute opioid tolerance or hyperalgesia in patients undergoing spinal fusion despite a significant difference in their mean intraoperative infusion rate of remifentanil (0.16 vs. 0.03 µg/kg/min) and a more extended period of remifentanil infusion which is twice our mean duration (averaging 220 vs. 107 min). Likewise, in a placebo-controlled, double-blind study among healthy human volunteers, a long duration (3 h) of remifentanil TCI of up to 4.00 ng/ml also failed to establish the development of significant tolerance to analgesia [14]. The absence of tolerance with remifentanil infusion was also observed in twenty healthy male volunteers who received a 3-hour continuous infusion of remifentanil (0.08 µg/kg/min) in a randomized study [15].

The findings of our study, however, did not concur with the result of a randomized study in paediatric scoliosis surgery which elucidated that a mean remifentanil dose of 0.28 µg/kg/min was associated with a larger amount of cumulative morphine consumption, up to 30.0% greater than the intermittent morphine group at 24-hour after surgery [3]. This was supported by another randomized study [16] whereby intraoperative remifentanil of 0.40 µg/kg/min triggered significant hyperalgesia as well as a higher amount of morphine consumption for 48 h postoperatively when compared to the group that received lower remifentanil dose of 0.05 µg/kg/min. A more recent retrospective study identified that infusion of remifentanil of > 0.2 µg/kg/min increases the probability of treatment-requiring pain for 48 h after robotic thyroid surgery when adjusting for analgesic consumption and its interaction with time [17].

OIH has a complex underlying cellular mechanism that is poorly understood [18]. Nevertheless, N-Methyl-D-aspartate (NMDA) receptors have been frequently described as playing a central role in the development of OIH, which is supported by various experimental studies performed in both humans and animals [19]. In accord with this theory, the co-administration of sub-anaesthetic doses (0.5 mg/kg) of NMDA-receptor antagonist ketamine during induction in our study could explain the non-significant difference observed in the postoperative pain and morphine consumption among the groups. This observation was consistent with those of Joly et al. [3] in which the use of ketamine completely averted the undesirable increase in postoperative pain sensitivity and hyperalgesia that otherwise resulted from large-dose remifentanil infusion. Likewise, patients who received a large dose of remifentanil of 0.40 µg/kg/min with ketamine had remarkably less postoperative morphine requirement than those receiving the same remifentanil dose but without ketamine [3].

While ketamine has been frequently reported and used by clinicians to prevent OIH, little is known previously about the use of paracetamol in preventing this phenomenon. A prospective, randomized, placebo-controlled trial comparing the effect of ketamine and paracetamol in ninety patients undergoing total abdominal hysterectomy concluded that the latter is as effective as the former in preventing remifentanil-induced hyperalgesia [20] In accord with this study, the use of pre-emptive intravenous paracetamol could have diminished the effects of hyperalgesia, and its co-administration with ketamine as described above could make the undesirable OIH even less pronounced in our study.

Furthermore, the implementation of multimodal analgesia in our routine practice could have improved pain control and reduced the need for morphine postoperatively. The use of multimodal analgesia has been proven to be equivalent to the conventional PCA for acute postoperative pain management in patients who underwent one or two-level posterior lumbar fusion surgery [21]. All our patients received regular oral paracetamol and cyclooxygenase-2 (COX-2) inhibitor (Celecoxib) in the postoperative period until discharge. As the use of opioids in the postoperative period can lead to the vicious cycle of OIH by activating the astroglia and microglia in the central nervous system [22], the use of opioid-sparing strategies are believed to be the most effective way of preventing OIH [23].

The use of COX-2 inhibitor is supported by a crossover study, in which pre-treatment with both parecoxib and ketorolac was found to reduce the area of hyperalgesia following remifentanil infusion, whereby more excellent effects were observed with selective COX-2 inhibition (parecoxib) than COX-1 inhibition (ketorolac) [24]. As both the enzymes are present in the spinal cord, their inhibition prevents glutamate stimulation that would otherwise lead to NMDA activation. Thus, it is plausible that systemic administration of COX inhibitors reduces OIH by direct action at the spinal cord level [25].

The divergent findings of OIH incidence in studies using remifentanil could be partly explained by the differences in the cumulative remifentanil dose used intraoperatively. A smaller cumulative dose of remifentanil with a mean of 28.70 ± 7.24 µg/kg in our study was considered insufficient to elicit hyperalgesia reliably, as suggested by Angst [2]. According to his analysis, the increase in opioid consumption and pain score was consistently reported in those studies in which the cumulative remifentanil dose was greater than 50 µg/kg and could not be reliably detected if smaller doses were administered.

In addition, the relatively shorter duration of remifentanil use in our study (mean 127.3 ± 26.3 min) could have attenuated the OIH and explained the reduced intensity in pain score and the lesser cumulative morphine consumption in the high dose remifentanil group. In a comparative study [13] using remifentanil as an adjuvant in general anaesthesia with sevoflurane or propofol in adults undergoing spinal fusion, Yeom et al. have failed to exhibit evidence of hyperalgesia and has concluded that their short duration of remifentanil infusion (averaging 216 min in sevoflurane/remifentanil group and 225 min in propofol/remifentanil group) as confounding factors. A recent and similar retrospective study [4] in adolescent idiopathic spine surgery also found no association between their long duration of remifentanil infusion with postoperative opioid consumption, despite the mean duration of 435 min, which is four times longer than ours.

Our study has several strengths. Our sample size is relatively large as compared to other similar retrospective studies done previously [4, 26]. Our patient’s selection was only in AIS patients, with the mean age of 14.0 ± 2.0 years, and recruited from a single tertiary institution to ensure homogeneity of our data. Our study also has several limitations. The retrospective nature of our research was subjected to registry bias when retrieving the data, in addition to the absence of a proper comparison or control group. For instance, the distribution of the Lenke curve types were not equal where there were more Lenke 5 and 6 curves in the high dose remifentanil group. Nonetheless, the surgical strategy in terms of instrumentation and correction were still similar in all Lenke curve types and in our opinion might not be an important confounding factor for the outcome of this study. The retrospective design also prevents accurate evaluation and diagnosis of hyperalgesia. The result of this study should not be over-interpreted and should be considered as hypothesis-generating due to the exploratory nature and the lack of power analysis. Ideally, a prospective randomized trial using clear separation of remifentanil dose (low dose versus high doses) should be designed in the future to study the causal relationship between remifentanil and opioid-induced hyperalgesia. The use of a sub-anaesthetic dose of ketamine, paracetamol, and postoperative multimodal analgesia could have been the confounding variables affecting the outcome. However, these were necessary and considered the current standard of care.

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